1. Field of the Invention
The present invention relates to a CDK-inhibiting pyrrolopyrimidine carboxamide derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating hepatocellular carcinoma comprising the same as an active ingredient.
2. Description of the Related Art
Hepatocellular carcinoma (HCC) is the most lethal disease to the liver cirrhosis patients. Hepatocellular carcinoma demonstrates the 6th highest onset rate in the whole world and the death rate of it takes the third place among cancers. 1.3 out of 100,000 people caught this disease in USA between 1978˜1980, which increased gradually to 3.3 people out of 100,000 between 1998˜2001. The increase of the onset rate continues year after year. A few decades ago, hepatitis C virus (HCV) infection was believed to be the major cause. However, since hepatitis B virus (HBV) infection was more widely distributed world-widely than hepatitis C virus infection, it has been suspected that HBV infection might be the major reason of hepatocellular carcinoma. The onset rate of this disease is higher in Asia or Africa than in Western countries. It is still very hard to treat hepatocellular carcinoma because hepatocellular carcinoma demonstrates the expressions of various drug-resistant genes and hence the sensitivity to chemotherapy is very low. In hepatocellular carcinoma cases, the Cdk (cyclin dependent kinase) activity in tissues and cells is very high suggesting that the intracellular Cdk inhibitors (p16Ink4, p21Waf1, p27Kip1, etc) are suppressed or those subclones which form conjugates with Cdk have abnormal activities. Because of those, Cdk inhibitors can be an excellent candidate group for treating hepatocellular carcinoma. Among those inhibitors, flavopiridol and roscovitine have been clinically tested.
Intracellular Cdk inhibitors (p16Ink4, p21Waf1, p27Kip1, etc) are involved in important check points of cell cycle to play an important role in regulating cell cycle. According to the previous reports, the division in G1/S or G2/M check point in cell cycle leads to uncontrollable cell growth, resulting in cancer or apoptosis. Therefore, to understand the mechanism of Cdk inhibitors is very important in treating cancer.
Cdk regulates cell cycle progression and gene transcription, which are two necessary factors for the cancer cell growth. Cdk induces phosphorylations of important molecules for cell cycle such as Rb protein, etc, to regulate the entry of each stage of cell cycle. Cdk forms heterodimers with cyclins to form a new complex having noble activity. For example, Cdk2/cyclin E is being a necessary factor for the entry of S phage of cell cycle, and Cdk2/cycline A is being a necessary factor to be a bridge between S phase and G2 phase. Cdk induces phosphorylation of carboxyl-terminal domain of RNA polymerase II large subunit, by which it regulates gene transcription. Human RNA polymerase II carboxyl-terminal domain contains 52 repeats of heptapeptide (YSPTSPS) that is easily phosphorylated. It is known that diverse Cdks can induce phosphorylation of such part. Two most representative Cdk complexes are Cdk7/cyclin H/Mat1 that is a part of TFIIH complex inducing transcriptional initiation and Cdk9/cyclin T that is also called P-TEFb involved in transcriptional elongation.
The present inventors have studied to synthesize a novel Cdk inhibitor compound. As a result, the inventors succeeded in the synthesis of pyrrolopyrimidine carboxamide derivative and at last completed this invention by confirming that the said pyrrolopyrimidine carboxamide derivative had excellent Cdk inhibiting effect in in vitro test and in animal test to be effectively used for preventing or treating hepatocellular carcinoma.